casein-kinase-ii and Schizophrenia

Recent genome-wide association studies (GWAS) have identified multiple risk loci that show strong associations with schizophrenia. However, pinpointing the potential causal genes at the reported loci remains a major challenge. Here we identify candidate causal genes for schizophrenia using an integrative genomic approach. Sherlock integrative analysis shows that ALMS1, GLT8D1, and CSNK2B are schizophrenia risk genes, which are validated using independent brain expression quantitative trait loci (eQTL) data and integrative analysis method (SMR). Consistently, gene expression analysis in schizophrenia cases and controls further supports the potential role of these three genes in the pathogenesis of schizophrenia. Finally, we show that GLT8D1 and CSNK2B knockdown promote the proliferation and inhibit the differentiation abilities of neural stem cells, and alter morphology and synaptic transmission of neurons. These convergent lines of evidence suggest that the ALMS1, CSNK2B, and GLT8D1 genes may be involved in pathophysiology of schizophrenia.

Topics: Animals; Brain; Casein Kinase II; Cell Cycle Proteins; Cell Differentiation; Cell Proliferation; Gene Knockdown Techniques; Genetic Predisposition to Disease; Glycosyltransferases; Humans; Mice; Mice, Inbred C57BL; Neural Stem Cells; Proteins; Quantitative Trait Loci; Schizophrenia

Mutations in the proline dehydrogenase gene

Topics: Aggression; Animals; Biological Clocks; Brain; Casein Kinase II; Drosophila melanogaster; Drosophila Proteins; Electrophysiological Phenomena; Humans; Male; Mitochondria; Neurons; Proline Oxidase; Protein Isoforms; Schizophrenia; Sequence Homology, Nucleic Acid

Schizophrenia has been described as a disease of the synapse. On the basis of previous studies reporting reductions in the levels and activity of CK2 (also know as casein kinase 2 or II) in the brain of subjects with schizophrenia, we hypothesized that CK2-mediated phosphorylation of the presynaptic protein syntaxin 1 (Stx 1) is deficient in schizophrenia. This in turn could affect the binding of Stx 1 to its protein partners and result in abnormal neurotransmitter release and synaptic transmission.. We analyzed post mortem prefrontal cortex samples from 15 schizophrenia cases and matched controls by quantitative immunoblotting.. In addition to replicating previous findings of reduced CK2 levels, we show that as predicted, the deficit in CK2 correlates with a deficit in phospho-Stx 1. In contrast, we find that these deficits are not present in depression cases. Further, we show that the reduced levels of CK2 and phospho-Stx 1 are not due to treatment with antipsychotic drugs (APDs). In fact, APDs seem to increase both CK2 and phospho-Stx 1, suggesting that their therapeutic action may be associated with the reversal of these deficits. Finally, we show that lower phospho-Stx 1 levels are associated with reduced binding of Stx 1 to SNAP-25 and MUNC18 and decreased SNARE complex formation.. Our findings constitute the first report of altered phosphorylation of a key component for neurotransmitter release in humans and suggest that regulation of Stx 1 by CK2-mediated phosphorylation could play a role in the pathophysiology of schizophrenia.

Topics: Adult; Aged; Aged, 80 and over; Animals; Antipsychotic Agents; Casein Kinase II; Cohort Studies; Female; Gene Expression Regulation; Humans; Immunoprecipitation; Male; Mice; Mice, Inbred C57BL; Middle Aged; Nucleolin; Phosphoproteins; Phosphoric Monoester Hydrolases; Phosphorylation; Postmortem Changes; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; RNA-Binding Proteins; Schizophrenia; SNARE Proteins; Syntaxin 1; Time Factors; Young Adult